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Review
. 2011 Aug;163(7):1365-78.
doi: 10.1111/j.1476-5381.2011.01365.x.

Prospects for Cannabinoid Therapies in Basal Ganglia Disorders

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Free PMC article
Review

Prospects for Cannabinoid Therapies in Basal Ganglia Disorders

Javier Fernández-Ruiz et al. Br J Pharmacol. .
Free PMC article

Abstract

Cannabinoids are promising medicines to slow down disease progression in neurodegenerative disorders including Parkinson's disease (PD) and Huntington's disease (HD), two of the most important disorders affecting the basal ganglia. Two pharmacological profiles have been proposed for cannabinoids being effective in these disorders. On the one hand, cannabinoids like Δ(9) -tetrahydrocannabinol or cannabidiol protect nigral or striatal neurons in experimental models of both disorders, in which oxidative injury is a prominent cytotoxic mechanism. This effect could be exerted, at least in part, through mechanisms independent of CB(1) and CB(2) receptors and involving the control of endogenous antioxidant defences. On the other hand, the activation of CB(2) receptors leads to a slower progression of neurodegeneration in both disorders. This effect would be exerted by limiting the toxicity of microglial cells for neurons and, in particular, by reducing the generation of proinflammatory factors. It is important to mention that CB(2) receptors have been identified in the healthy brain, mainly in glial elements and, to a lesser extent, in certain subpopulations of neurons, and that they are dramatically up-regulated in response to damaging stimuli, which supports the idea that the cannabinoid system behaves as an endogenous neuroprotective system. This CB(2) receptor up-regulation has been found in many neurodegenerative disorders including HD and PD, which supports the beneficial effects found for CB(2) receptor agonists in both disorders. In conclusion, the evidence reported so far supports that those cannabinoids having antioxidant properties and/or capability to activate CB(2) receptors may represent promising therapeutic agents in HD and PD, thus deserving a prompt clinical evaluation.

Figures

Figure 1
Figure 1
Diagram showing the most important neuronal pathways involved in the basal ganglia function. The neuronal subpopulations that are affected in the two pathologies reviewed in this article, Huntington's disease and Parkinson's disease, are indicated by arrows. DA, dopamine; GABA, γ-aminobutiric acid; GLU, glutamate.
Figure 2
Figure 2
Comparison of CB1 and CB2 receptor changes during presymptomatic and symptomatic phases in experimental models of Huntington's disease and Parkinson's disease.
Figure 3
Figure 3
Chemical structures of representative cannabinoid compounds having cannabinoid receptor-independent antioxidant properties. The phenolic moiety responsible of this antioxidant effect is indicated with a green square. Δ9-THC, Δ9-tetrahydrocannabinol; Δ9-THCV, Δ9-tetrahydrocannabivarin.
Figure 4
Figure 4
Mechanisms proposed for the neuroprotective effects exerted by cannabinoids against oxidative injury that occurs in most neurodegenerative disorders, including HD and PD. These neuroprotective effects involve mainly CB1 and CB2 receptor-independent mechanisms. COX, cyclooxygenase; DA, dopamine; DOPAC, dihydroxyphenylacetic acid; ER, endoplasmic reticulum; iNOS, inducible nitric oxide synthase; LOX, lipoxygenase; MAO, monoamine oxidase; nrf-2, nuclear factor-erythroid 2-related factor 2; ROS, reactive oxygen species.
Figure 5
Figure 5
Mechanisms proposed for the neuroprotective effects exerted by cannabinoids against inflammatory events that occur in most neurodegenerative disorders, including Huntington's disease and Parkinson's disease. These neuroprotective effects involve mainly the activation of CB2 receptors located in glial cells (reactive microglia and/or astrocytes). COX-2: cyclooxygenase type-2; iNOS, inducible nitric oxide.

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